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Fred Saad: Hello, I'm Professor Fred Saad from the University of Montreal in Canada. On behalf of my co-authors, it's my pleasure to present a summary of our review article, Olaparib Monotherapy or in Combination with Abiraterone for the Treatment of Patients with Metastatic Castration-Resistant Prostate Cancer and a BRCA Mutation, which we published in the journal Targeted Oncology.

PARP inhibitors such as olaparib have pioneered a new treatment paradigm in the mCRPC setting for patients with BRCA1 or BRCA2 mutations. In our article, we summarized the key clinical and safety outcomes for olaparib specifically in patients with these BRCA mutations. We focused on the findings from two pivotal trials in the development and subsequent regulatory approval of olaparib, the PROfound trial of olaparib monotherapy and the PROpel trial of olaparib in combination with abiraterone.

PROfound was the first Phase III study to demonstrate the efficacy of a PARP inhibitor in a biomarker-selected mCRPC population who had progressed on an androgen receptor pathway inhibitor or ARPI. In cohort A, which included patients with only BRCA1, BRCA2, or ATM mutations, as well as the overall trial population, including patients with 15 pre-specified homologous recombination repair mutations, treatment with olaparib led to a significantly longer radiographic progression-free survival, rPFS, than the control arm where participants received physician's choice of enzalutamide or abiraterone.

In the subgroup of patients with BRCA1 and/or BRCA2 mutations, rPFS was 6.8 months longer for those receiving olaparib than for those in the control arm. Median rPFS was 9.8 versus three months respectively, resulting in a 78% risk reduction. As shown in this Kaplan-Meier curve, at 59% maturity, overall survival was longer in the olaparib than in the control arm. Median OS in the olaparib arm was 20.1 months versus 14.4 months in the control arm, representing a 5.7 month improvement and a 37% risk reduction.

The other trial we discussed, PROpel, assessed the combination of olaparib plus abiraterone in a broader, biomarker-unselected first-line mCRPC population. This study also met its primary endpoint and demonstrated a statistically significant and clinically meaningful rPFS benefit with olaparib plus abiraterone versus placebo plus abiraterone according to investigator assessment in the intention to treat population. Post hoc exploratory analysis for patients with BRCA mutations showed that the combination of olaparib plus abiraterone had a clinically meaningful benefit over placebo plus abiraterone for both rPFS and OS.

Median investigator assessed rPFS was not reached for olaparib plus abiraterone, and only 8.4 months for placebo plus abiraterone resulting in a 77% risk reduction. As shown in this Kaplan-Meier curve, at 45% maturity, median OS was not reached for patients with BRCA mutation receiving olaparib plus abiraterone versus 23 months for those receiving placebo plus abiraterone resulting in a 71% risk reduction. After three years, 71% of the patients in the olaparib plus abiraterone arm versus only 28% in the placebo plus abiraterone arm were alive.

Phase two clinical data from TOPARP-B and BRCAAway trials, which included patients with BRCA mCRPC additionally support the benefit of olaparib as monotherapy or in combination with abiraterone in this patient population. Both trials showed with high response rates and prolonged rPFS in patients receiving olaparib or olaparib plus abiraterone respectively. In TOPARP-B, where participants received olaparib following one or two taxane chemotherapy regimens, median rPFS was 8.3 months.

And in the BRCAAway which investigated olaparib plus abiraterone in first-line mCRPC patients, median RPFS was 39 months. The safety profile observed in patients with BRCA mutations in both PROfound and PROpel was consistent with that observed in the respective ITT populations. Anemia was the most common side effect in the olaparib arm of both PROfound and PROpel. And most anemia events occurred during the first two months of treatment and were manageable with supportive standard care, not precluding continued treatment with olaparib in most patients.

In conclusion, our review highlights that olaparib, both on its own and in combination with abiraterone, results in substantial clinical benefit for patients with BRCA mCRPC, delaying disease progression and improving survival over standard treatments with no new safety signals. These findings support the integration of olaparib early in the treatment sequence for patients with BRCA mutations and mCRPC. Our findings also highlight the importance of early and comprehensive genetic testing to identify patients with BRCA mutations who may derive greatest benefit from PARP inhibitors such as olaparib.

My co-authors and I would like to thank all of the patients, their families, and caregivers, and the investigators and staff who have participated in these trials. Thank you very much for listening.